Mood Disorders

1
Mood Disorders

• The two principal mood disorders are Major
  Depression and Bipolar Disease.
• Characteristics
• Morbidity (slides from Tom Insel)
• Many brain systems malfunction in Major
  Depression and no single cause has been
  identified. However, treatment of malfunctioning
  biogenic amine systems in the brain, especially
  the serotonergic systems relieves symptoms in
  many individuals.
• One class of highly effective antidepressants
  (SSRIs) block reuptake of serotonin.
• Aminergic systems in the brain
• Midbrain Raphe nuclei (5-HT)
• Locus coeruleus (NE)
• Dopaminergic systems
• How does blockade of serotonin reuptake relieve
  depression? - not yet thoroughly understood.
• Neurotrophic hypothesis

2
Disclaimer This lecture deals with psychiatric
disease. Professors Kennedy, Lester, and Adolphs
are not psychiatrists--not even
physicians. Dont change any medical treatment
that you might now be receiving on the basis of
these lectures. Dont give any medical advice
based on these lectures or problem sets.
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Major Depression

• Symptoms Depression is defined as the affective
  state of sadness that occurs in response to a
  variety of human situations such as loss of a
  loved one, failure to achieve goals, or
  disappointment in love. Major depression differs
  only in intensity and duration or quality of the
  emotional state.

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• II. Characteristics of Major Depression
• Untreated episodes of major depression usually
  last from 7 - 14 months.
• Major depression is a recurring disorder, usually
  worsening with age if not treated.
• The reported incidence of depression is 3 times
  higher in women than in men.

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Characteristics of Bipolar Disorder
(Manic-Depressive Disorder)

• Alternation between periods of mania and
  depression
• Mania is defined as an affective state of
  elation, almost the opposite of depression
• Individuals feel faultless, full of fun, bursting
  with energy.
• Need for sleep is usually reduced.
• More talkative than usual subjectively
  experience racing thoughts and ideas.
• Tend to make impulsive decisions of the grandiose
  sort and have unlimited confidence in themselves.
• Tend to become involved in activities that have a
  high potential for negative consequences that go
  unrecognized.
• Some manic individuals are capable of highly
  productive efforts when channeled appropriately
  (hypomania).
• In others the predominant mood is irritability,
  belligerence, and impatience.

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Touched With Fire Manic Depressive Illness and
the Artistic Temperament by Kay Redfield Jamison
"This is meant to be an illustrative rather than
a comprehensive list . . .Most of the writers,
composers, and artists are American, British,
European, Irish, or Russian all are deceased . .
. Many if not most of these writers, artists, and
composers had other major problems as well, such
as medical illnesses, alcoholism or drug
addiction, or exceptionally difficult life
circumstances. They are listed here as having
suffered from a mood disorder because their mood
symptoms predated their other conditions, because
the nature and course of their mood and behavior
symptoms were consistent with a diagnosis of an
independently existing affective illness, and/or
because their family histories of depression,
manic-depressive illness, and suicide--coupled
with their own symptoms--were sufficiently strong
to warrant their inclusion."
autobiography An Unquiet Mind by Kay Redfield
Jamison
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from Jamison KEYH Asylum or psychiatric
hospital S Suicide SA Suicide Attempt
Writers Hans Christian Andersen, Honore de
Balzac, James Barrie, William Faulkner (H), F.
Scott Fitzgerald (H), Ernest Hemingway (H, S),
Hermann Hesse (H, SA), Henrik Ibsen, Henry James,
William James, Samuel Clemens (Mark Twain),
Joseph Conrad (SA), Charles Dickens, Isak Dinesen
(SA), Ralph Waldo Emerson, Herman Melville,
Eugene O'Neill (H, SA), Mary Shelley, Robert
Louis Stevenson, Leo Tolstoy, Tennessee Williams
(H), Mary Wollstonecraft (SA), Virginia Woolf (H,
S) Composers Hector Berlioz (SA), Anton
Bruckner (H), George Frederic Handel, Gustav
Holst, Charles Ives, Gustav Mahler, Modest
Mussorgsky, Sergey Rachmaninoff, Giocchino
Rossini, Robert Schumann (H, SA), Alexander
Scriabin, Peter Tchaikovsky Nonclassical
composers and musicians Irving Berlin (H), Noel
Coward, Stephen Foster, Charles Mingus (H),
Charles Parker (H, SA), Cole Porter (H) Poets
William Blake, Robert Burns, George Gordon, Lord
Byron, Samuel Taylor Coleridge, Hart Crane (S) ,
Emily Dickinson, T.S. Eliot (H), Oliver
Goldsmith, Gerard Manley Hopkins, Victor Hugo,
Samuel Johnson, John Keats, Vachel Lindsay (S),
James Russell Lowell, Robert Lowell (H), Edna St.
Vincent Millay (H), Boris Pasternak (H), Sylvia
Plath (H, S), Edgar Allan Poe (SA), Ezra Pound
(H), Anne Sexton (H, S), Percy Bysshe Shelley
(SA), Alfred, Lord Tennyson, Dylan Thomas, Walt
Whitman Artists Richard Dadd (H), Thomas
Eakins, Paul Gauguin (SA), Vincent van Gogh (H,
S), Ernst Ludwig Kirchner (H, S), Edward Lear,
Michelangelo, Edvard Meunch (H), Georgia O'Keeffe
(H), George Romney, Dante Gabriel Rossetti (SA)
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Vincent Van Gogh 1853-1890 750 paintings
1600 drawings 700 letters Life
history born and raised in the Netherlands Paris
1886-88 Arles 1888 (1st episode cut off his own
ear) hospitalized 1888-1890 Auvers-sur-Oise 3
months. Shot himself 7/27/1890
1887-88
1886
1887
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I should like to do portraits which will appear
as revelations to people in a hundred years'
time.-- Letter to his sister Wil, 3 June 1890
Dr. Gachet June 1890
Early 1889
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July 1890
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(No Transcript)
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Suicide in America
Approx 30,000 suicides/year (approx 18,000
homicides)
Third leading cause of death in adolescence
Males outnumber females by 41
90 have mental disorder
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National Comorbidity Survey
(Kessler et al. JAMA, 2003)
Face-to-face household survey of 9090 Americans gt
age 17
Prevalence 1 year 6.6 (13.1-14.2
million) lifetime 16.2(32.6 35.1
million) 50 rated as severe or very severe 75
with co-morbid psychiatric dx
Impairment Mean days out of work/role in past
year Mild 2.8 Mod. 11.4 Severe
33.1 Very sev. 96.5
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Disease Burden by Illness - DALY United States,
Canada and Western Europe, 200015-44 year olds
(Disability Adjusted Life Years)
Unipolar depressive disorders Alcohol use
disorders Schizophrenia Iron-deficiency
anemia Bipolar affective disorder Hearing loss,
adult onset HIV/AIDS Chronic OPD Osteoarthritis Ro
ad traffic accidents
0 2 4 6 8 10 16
Source WHO World Health Report, 2001
15
Depression is Treatable
Somatic Treatments (Meds, rTMS, ECT)
Psychotherapy (CBT, IPT)
Other (diet, exercise, etc.)
16
Caltech Counseling Center Depression/Suicide
Website
http//www.counseling.caltech.edu/Suicid-Depress.h
tml
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Depression involves dysfunction of many brain
areas

• Along with changes in mood, the symptoms of
  Major Depression and Bipolar Disorder include
  disruption of basic drives (eating and sleeping),
  as well as cognitive disturbances (ruminations,
  guilt, indecisiveness, persistent thoughts of
  suicide).
• This constellation of symptoms suggest
  involvement of cortical structures, a number of
  limbic brain structures, including the
  hippocampus, amygdala, and mesolimbic dopamine
  neurons (reward centers), and also midbrain
  structures controlling appetite.

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Brain Areas that Regulate Mood
FC Frontal cortex (esp. prefrontal and
cingulate) - cognitive function, attention HP
Ventral Hippocampus - cognitive function,
memory NAc Nucleus Accumbens (ventral striatum)
- reward and aversion Amy Amygdala - mediates
responses to emotional stimuli HYP Hypothalamus
regulates sleep, appetite, energy, sex VTA
Ventral Tegmental Area - Sends dopaminergic
projections to other areas DR Dorsal Raphe
nuclei - send serotonergic input to other
areas LC Locus Coeruleus - sends noradrenergic
input to other areas.
From Berton and Nestler, Nature Reviews
Neuroscience, 7 137, 2006
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SSRIs

• The most successful medicines for treatment of
  Major Depression in recent years have been the
  selective serotonin reuptake inhibitors (SSRIs)
• SSRIs include Prozac, Zoloft, Celexa, Paxil
  These drugs inhibit the specific serotonin
  transporters that take up serotonin after it is
  released. Thus, the drugs are believed to
  increase serotonin levels in the brain.
• Depression also is accompanied by misregulation
  of other neurohormonal pathways, for example the
  ACTH (pituitary) /cortisol (adrenal gland)
  pathway. NE and DA systems may also be
  misregulated.
• The SSRIs are not effective for about half of
  cases of depression. Thus, we have much more to
  learn about the various causes of depression.

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Depression involves derangement of Biogenic Amine
pathways

• The biogenic amines are a group of amine
  neurohormones that are usually modulatory in
  their action.
• Serotonin or 5-hydroxytryptamine (5-HT)

5-HT
B. Norepinephrine or noradrenaline
NE
C. Dopamine
DA
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General Characteristics of Brain Neuromodulatory
Systems

• Cell bodies (somas) reside in clusters of
  relatively small mid-brain nuclei.
• Axons project widely throughout the brain and
  spinal cord. However, the precise patterns of
  connections are distinct among different
  neuromodulatory systems.
• A subset of axons from these nuclei do not form
  tight synapses with a structural link to a
  receiving cell. Instead they contain release
  sites that release their neurohormone(s) in such
  a way that they bathe the surrounding neurons.
• Most biogenic amine hormone synapses also contain
  one or more co-transmitter such as a peptide
  hormone. Thus, two different modulators are
  co-released.
• Many aspects of the function of these systems are
  still not understood.

22
Serotonergic systems in the brain
Rostral System
Caudal System
The midbrain Raphe nuclei
from Feldman et al., Principles of
Neuropsychopharmacology, Sinauer, 1997
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Rostral System
B6 and B7 are the Dorsal Raphe nuclei, which
contain 5-HT neurons whose endings branch
profusely and do not make conventional
synapses. This fiber system is called the
D-system.
B5 and B8 are the Median Raphe nuclei, which
contain 5-HT neurons whose endings form repeated,
more conventional synapses. This fiber system is
called the M system.
B9 is also called the supralemniscal nucleus
(SLN).
from Feldman et al., Principles of
Neuropsychopharmacology, Sinauer, 1997
24
Two Serotonergic Fiber Types in the Forebrain
Demonstrated by Immunocytochemical Labeling
D-System - small arrows M-System - large arrows
Scale bar 10 µm
from Tork, Ann. N.Y. Acad. Sci., 1990
25
Volume Transmission
D-system release sites show no synaptic
specialization and are believed to release
serotonin diffusely around nearby neurons. This
form of chemical communication is sometimes
called volume transmission.
Some of the noradrenergic and dopaminergic
fibers, as well as many peptidergic fibers, also
are believed to transmit in this way.
Note that many terminals of both conventional and
volume-transmitting type contain more than one
transmitter, often an amine and a peptide, for
example.
These systems are believed to mediate large scale
modulation of brain circuits. The control and
functions of these pathways are not yet well
understood.
26
Noradrenergic Systems in the CNS
Red box denotes the Locus coeruleus
from Feldman et al., Principles of
Neuropsychopharmacology, Sinauer, 1997
27
Dopaminergic systems in the CNS
from Feldman et al., Principles of
Neuropsychopharmacology, Sinauer, 1997
28
Why does blockade of serotonin reuptake relieve
depression?

• Possible downstream consequences of misregulation
  of serotonergic systems
• Short term derangement of modulation of synaptic
  strength and possibly also of neuronal intrinsic
  properties.
• Long term change in modulation of neuronal gene
  expression.
• The clinical observation that anti-depressants
  usually take a few weeks to a month to have full
  efficacy suggests that modulation of gene
  expression plays the dominant role.

29
An effect of 5-HT in the hippocampus
Activation of the 5-HT receptor on pyramidal
cells hyperpolarizes the membrane, as does
baclofen, an agonist of GABAB receptors.
Effects of both the 5-HT receptor and the GABAB
receptor are blocked by pertussis toxin (PTX),
which inactivates a class of G-proteins.
from Andrade and Chaput, 1991
30
Short term actions of serotonin modulate many
behaviors

• Serotonergic neurons are known to be activated or
  inhibited in different nuclei by a wide variety
  of stimuli and to play a role in a variety of
  behaviors, including
• Sleep-waking cycle, and sleep states.
• Feeding
• Aggression
• Spatial and sensory orientation

31
Neurotrophic Hypothesis
Duman and Monteggia, Biol. Psych. (2006)
591116-1127
32
Postulated Role for Brain-derived Neurotrophic
Factor (BDNF) in Depression
Some evidence suggests that enhancing the
monoaminergic system acts to increase nuclear
expression of BDNF. This, in turn ameliorates
some of the structural effects of major
depression.
From Berton and Nestler, Nature Reviews
Neuroscience, 7 137, 2006
33
In adult animals, new neurons are formed
continuously from progenitor cells located in the
subgranular zone (SGV) Those neurons
differentiate and become incorporated into
neuronal circuits in the dentate gyrus
Neurogenesis in the SGV
Warner-Schmidt and Duman (2006) Hippocampus 16
239
34

• Stress and anti-depressants have opposing effects
  on
• Neurogenesis in the SGZ of the dentate gyrus
• Production of VEGF and BDNF in the cortex and
  hippocampus

VEGF increases proliferation in SGZ BDNF
increases neuronal survival
Duman and Monteggia, Biol. Psych. (2006)
591116-1127
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Mood Disorders

• The two principal mood disorders are Major
  Depression and Bipolar Disease.
• Characteristics
• Morbidity (slides from Tom Insel)
• Many brain systems malfunction in Major
  Depression and no single cause has been
  identified. However, treatment of malfunctioning
  biogenic amine systems in the brain, especially
  the serotonergic systems relieves symptoms in
  many individuals.
• One class of highly effective antidepressants
  (SSRIs) block reuptake of serotonin.
• Aminergic systems in the brain
• Midbrain Raphe nuclei (5-HT)
• Locus coeruleus (NE)
• Dopaminergic systems
• How does blockade of serotonin reuptake relieve
  depression? - not yet thoroughly understood.
• Neurotrophic hypothesis
• Genetic studies suggest a mutation in a serotonin
  transporter may increase susceptibility to
  depression.